Project: Medicines with strongly enhanced in vivo stability, optimal receptor interaction, and early indication of clinical success.

BACKGROUND: PEPTIDE THERAPEUTIC MARKET AND COMMERCIAL OPPORTUNITY FOR PEPTIDE STABILIZATION_x000D_Peptide therapeutics are a commercially increasingly important class of drugs. In 2010 several single peptides had annual sales of over 1 B$. Peptides are entering clinical studies in a broad range of therapeutic categories. In spite of the increasing medical and commercial success of peptide therapeutics, a major drawback of using peptides is their rapid degradation in the body by peptidases, thereby strongly reducing bioavailability and precluding oral delivery. Instability is the CO bottleneck for developing efficacious therapeutic peptides and there is a strong need for technologies that can prevent this degradation by stabilizing the peptides. The large financial opportunity associated with this need is illustrated by the occurrence in 2010 of a deal on peptide stabilization technology, with a total value of 1.1 B$. Stabilized peptides are suitable for oral delivery. The large market opportunity for oral delivery of peptides is illustrated by the occurrence of a 150 M€ transaction in 2008 for development of orally deliverable peptides. Technical proof of principle has been obtained for the oral delivery, high therapeutic activity in case of heart failure and acute respiratory distress syndrome of LanthioPep’s lanthionine-stabilized angiotensin-(1-7) and commercial proof of principle by its out-licensing to Tarix. In short:_x000D_• Tremendously large and growing market, hundreds of economically and medically important peptides_x000D_• Large commercial opportunity to stabilize peptides _x000D_• Starting basis of technical and commercial proof of principle _x000D__x000D_PROJECT GOALS: _x000D_A) GENERATING A PLATFORM TECHNOLOGY TO STABILIZE PEPTIDES._x000D_This project aims at generating a broadly applicable platform technology which strongly improves the physiological half-life of peptides. The aimed for technology platform introduces lanthionine cross-links at predetermined sites and also comprises a powerful display and screening system for optimal lanthionine-bridged peptides. The stabilization essentially works as follows. Peptides can be simply compared with a chain of “beads”, amino acids. In the human body “pacmen”, peptidases, cut sites of the chain linking the beads. The stabilization technology introduces in a controlled way an additional very strong and highly specific link between two beads, which are 2-10 beads remote from each other in the chain thus yielding cyclization(s). As a result the “pacmen” cannot cut any more the chain linking the beads. Apparently they “cannot get the cyclized bead chain in their mouth”. In this way peptides are stabilized. Specific goals for aspects of the peptide stabilization technology: _x000D_• Applicability to a broad range of peptides yielding intrinsic in vivo stability. _x000D_• Enabling optimal interaction between a peptide and its receptor._x000D_• Easy generation of variants and libraries of peptides._x000D_• Display and screening system to easy identify optimal peptides. _x000D_• Feasibility to choose for chemical or biological bulk production._x000D_• Start of clinical trials for one (outlicensed) lead peptide._x000D__x000D_B) EARLY VALUE GENERATION OF STABILIZED PEPTIDES BY A PLATFORM TECHNOLOGY FOR ASSESSING CLINICAL PERSPECTIVES._x000D_Lanthionine-stabilized peptides are new chemical entities. They have to be developed through clinical phases, which is a tremendously costly process. Therefore lanthionine-stabilized peptides will gain strongly increased value when knowing as early as possible which of them will have good chances to be successful in clinical trials. Therefore we will generate a unique validation platform. This label-free holistic platform technology uses real time activity measurements simultaneously involving distinct receptor pathways in human cells. The system can simply be explained as follows. A specific light beam is passing from below through cultured human cells. When a peptide binds a receptor a signal is transmitted which leads to migration of light-recepting molecules, technically called “dynamic mass redistribution”. This molecular redistribution reflects which receptor pathway is activated. This can be used to study which receptor(s) a lanthionine-stabilized peptide activates and how effectively. This is of crucial importance since the lanthionine-stabilization may modulate the receptor specificity and may yield either variants with reduced or unwanted activity or optimal variants with enhanced activity and enhanced specificity. This validating platform technology will have important advantages: _x000D_• Use of human cells, precluding errors due to differences between man and animal._x000D_• Label free, precluding artifacts due to labeling_x000D_• Measurements in real-time, precluding wrong interpretation of indirect effects. _x000D_• Optimal picture of receptor specificity since multiple receptor-pathways in the cells are simultaneously monitored._x000D_• REDUCTION OF THE DEPENDENCE ON ANIMAL EXPERIMENTS BY MORE EFFECTIVE PRE-IN VIVO LEAD SELECTION._x000D_

Acronym	ThioPep-DMR (Reference Number: 6877)
Duration	02/01/2012 - 30/06/2014
Project Topic	This project addresses the large market opportunity for an innovative therapeutic peptide stabilization platform technology and adds further value by early selection for high chance for clinical success via a real-time, label-free, complete pathway activation picture in human cells.
Project Results (after finalisation)	A collection of lanthionine-stabilized peptides made available by Lanthio Pharma, Netherlands, were investigated on their activation of G-protein coupled receptors applying the Dynamic Mass Redistribution (DMR) technology and classical second messenger assays._x000D_(1) In vitro assays of lanthionine-stabilized angiotensin II-derivatives lead to results valuably supporting literature and in vivo data from Lanthio Pharma aiming at a contemporary launching of one lanthi-angiotensin II variant to clinical studies. That variant turned out to be selective for the angiotensin II-type 2 receptor , as determined by DMR._x000D_(2) Based on results from DMR an early selection of lanthionine-stabilized apelin- and neuropeptide G-derivatives was achieved with respect to their future development as therapeutics either for the treatment of heart failure and related diseases or as neurotherapeuticals, respectively. In the course of these investigations, certain characteristics of receptor activation by the lanthi-apelins were uncovered by DMR, which are undetected in classical GPCR assays, and a tendency of being selective towards the neuropeptide G-receptor 2 was found for two lanthi-neuropeptide G variants._x000D_(3) The DMR-technology was successfully established as a platform method for the validation of lanthionine-peptide mediated activation of G protein-coupled receptors._x000D_
Network	Eurostars
Call	Eurostars Cut-Off 7

Project partner

Number	Name	Role	Country
2	LanthioPep	Coordinator	Netherlands
2	University of Bonn, Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology	Partner	Germany